The present invention relates to a composition comprising a novel azole-based compound having an anti-fungal action and a saccharide, which is used in the fields of medicine etc.
Various azole compounds having an antifungal action have hitherto been known. For example, Japanese Patent Kokai Publication No. Hei 6-293740 discloses an azole compound represented by the formula: 
(wherein Ar is a substituted phenyl group; R1 and R2 independently are a hydrogen atom or a lower alkyl group, or R1 and R2 may combine together to form a lower alkylene group; R3 is a group bonded through a carbon atom; R4 is a hydrogen atom or an acyl group; X is a nitrogen atom or a methine group; and Y and Z independently are a nitrogen atom or a methine group which may optionally be substituted with a lower alkyl group) or a salt thereof. Japanese Patent Kokai Publication No. Hei 8-104676 discloses a compound represented by the formula: 
(wherein Ar is an optionally substituted phenyl; R1 and R2 are, the same or different, a hydrogen atom or a lower alkyl group, or R1 and R2 may combine together to form a lower alkylene group; R3 is a hydrogen atom or an acyl group; Y is a nitrogen atom or a methine group; and A is an optionally-substituted saturated cyclic amide group bonded through a first nitrogen atom) and a salt thereof. WO 9625410 A1 (corresponding to Japanese Patent Kokai Publication No. Hei 9-183769) discloses a compound represented by the formula: 
[wherein Ar is an optionally substituted phenyl group; R1 and R2, the same or different, are a hydrogen atom or a lower alkyl group, or R1 and R2 may combine together to form a lower alkylene group; R3 is a hydrogen atom or an acyl group; X is a nitrogen atom or a methine group; A is Yxe2x95x90Z (Y and Z, the same or different, are a nitrogen atom or a methine group optionally substituted with a lower alkyl group) or an ethylene group optionally substituted with a lower alkyl group; n is an integer of 0 to 2; and Az is an optionally substituted azolyl group] or a salt thereof.
On the other hand, a series of compounds referred to as a soft drug have hitherto been known as a quaternary ammonium salt type derivative of an azole (imidazole, triazole) compound which is hydrolyzed enzymatically and/or non-enzymatically. For example, quaternary ammonium salt derivatives of 1-methylimidazole are reported in Journal of Medicinal Chemistry, Vol. 23, page 469, 1980 (antibacterial activity), ibid., Vol. 23, 566, 1980 (antitumor activity), ibid., Vol. 23, 474, 1980 (anticholinergic activity) and ibid., Vol. 32, 493, 1989 (acetylcholine esterase reactivation activity), and these quaternary salts themselves have a biological activity and it is one of their features that hydrolysis thereof occurs rapidly. On the other hand, a quaternary ammonium salt type derivative of azole compounds as a kind of prodrug has been reported only in Pharmaceutical Research Vol. 9, page 372, 1992 (antiglaucoma drug) and Entomologia Experimentalis et Aplicata, Vol. 44, page 295, 1987 (insecticide). In addition, an example of use as a synthetic intermediate of a quaternary ammonium type derivative of imidazole, utilizing its easily hydrolysable property, is reported in Journal of Chemical Society Perkin I, page 1341, 1979 and New Journal of Chemistry, Vol. 16, page 107, 1992. Moreover, a series of quaternary ammonium salt type-derivatives are described in U.S. Pat. Nos. 4,061,722 and 4,160,099. However, enzymatically and/or non-enzymatically hydrolyzed quaternary salt derivatives of the azole compounds having an antifungal activity have never been known.
These azole-based compounds having an anti-fungal action are neither necessarily sufficient in respect of their solubility in e.g. water for use as injection nor sufficiently satisfactory in respect of the absorption thereof into a living body for demonstrating a high therapeutic effect, and thus there is a need for improvements in the solubility thereof in water and for improvements in the absorption thereof into a living body. Further, there is a need for a pharmaceutical preparation for injection stably containing an azole compound having an anti-fungal action.
As a result of their extensive study under the circumstances described above, the present inventors found that those derivatives derived from azole-based compounds by quaternarizing nitrogen atoms contained in 1H-imidazole-1-yl group or 1H-1,2,4-triazole-1-yl group thereof have improved solubility in water and are hydrolyzed enzymatically and/or non-enzymatically in vivo to form those compounds having 1H-imidazole-1-yl group or 1H-1,2,4-triazole-1-yl group and having an anti-fungal activity, that the stability of said compounds is improved by adding saccharides to said compounds, and that lyophilization of compositions containing said compounds and saccharides can give rise to further stable lyophilized products, and on the basis of these findings, the present invention was completed.
That is, the present invention relates to:
(1) A composition comprising a quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound wherein one of the nitrogen atoms constituting the azole ring is quaternized with a group eliminating in vivo and represented by the formula: 
wherein R1 represents a hydrocarbon or heterocyclic group which may be substituted, R2 represents a hydrogen atom or a lower alkyl group, and n is 0 or 1, and a saccharide, said compound being capable of being converted into an anti-fungal azole compound upon elimination of said group in vivo;
(2) The composition according to item (1) above, which is a lyophilized product;
(3) The composition according to item (1) or (2) above, wherein the quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound is a compound represented by the formula: 
wherein X represents a nitrogen atom or a methine group, Ar represents a phenyl group which may be substituted, A represents a hydrocarbon or heterocyclic group which may be substituted, X1 represents an oxygen atom or a methylene group, X2 represents a sulfur atom which may be oxidized, m and p each represents 0 or 1, and Yxe2x88x92 represents an anion, (1) R3, R4 and R5 are the same or different and each represents a hydrogen atom or a lower alkyl group, (2) R3 represents a hydrogen atom or a lower alkyl group, and R4 and R5 are combined to form a lower alkylene group, or (3) R5 represents a hydrogen atom or a lower alkyl group, and R3 and R4 are combined to form a lower alkylene group, and other symbols have the same meanings as defined above;
(4) The composition according to item (1) or (2) above, wherein the quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound is 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolydinyl]butyl]-1H-1,2,4-triazolium chloride;
(5) The composition according to item (1) or (2) above, which is an anti-fungal agent;
(6) The composition according to item (1) or (2) above, wherein the saccharide is a monosaccharide, a disaccharide or sugar alcohol;
(7) The composition according to item (1) or (2) above, wherein the saccharide is fructose, glucose, maltose, cellobiose, gentiobiose, melibiose, lactose, turanose, sophorose, trehalose, isotrehalose, isosaccharose, white sugar, mannitol, sorbitol, xylitol or inositol;
(8) The composition according to item (1) or (2) above, wherein the saccharide is maltose, lactose, white sugar, mannitol, trehalose or inositol;
(9) The composition according to item (1) or (2) above, wherein the saccharide is inositol or trehalose;
(10) The composition according to item (1) or (2) above, wherein the saccharide is contained in an amount of 0.001 to 1000 parts by weight per 1 part by weight of the quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound;
(11) The composition according to item (1) or (2) above, wherein the saccharide is contained in an amount of 0.01 to 100 parts by weight per 1 part by weight of the quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound;
(12) The composition according to item (1) or (2) above, wherein the saccharide is contained in an amount of 0.1 to 10 parts by weight per 1 part by weight of the quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound;
(13) The composition according to item (1) or (2) above, which is a pharmaceutical preparation for injection;
(14) A process for producing a lyophilized product, which comprises adding a saccharide to an aqueous solution of a quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound wherein one of the nitrogen atoms constituting the azole ring is quaternized with a group of formula (II) eliminating in vivo, and then lyophilizing the mixture, said compound being capable of being converted into an anti-fungal azole compound upon elimination of said group in vivo;
(15) A method of stabilizing a quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound in a lyophilized product, which comprises adding a saccharide to an aqueous solution of a quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound wherein one of the nitrogen atoms constituting the azole ring is quaternized with a group of formula (II) eliminating in vivo, and then lyophilizing the mixture, said compound being capable of being converted into an anti-fungal azole compound upon elimination of said group in vivo;
(16) Use of a saccharide as an additive in a composition for stabilizing a quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound wherein one of the nitrogen atoms constituting the azole ring is quaternized with a group of formula (II) eliminating in vivo, said compound being capable of being converted into an anti-fungal azole compound upon elimination of said group in vivo; and
(17) Use of a composition for production of a pharmaceutical preparation for injection, said composition comprising a quaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound wherein one of the nitrogen atoms constituting the azole ring is quaternized with a group of formula (II) eliminating in vivo, and a saccharide, said compound being capable of being converted into an anti-fungal azole compound upon elimination of said group in vivo.
The xe2x80x9cquaternized nitrogen-containing imidazole-1-yl or 1,2,4-triazole-1-yl compound wherein one of the nitrogen atoms constituting the azole ring is quaternized with a group of formula (II) eliminating in vivo, said compound being capable of being converted into an anti-fungal azole compound upon elimination of said group in vivoxe2x80x9d (also referred to hereinafter as compound (I)) is a compound having an imidazole-1-yl or 1,2,4-triazole-1-yl group in the molecule, wherein a nitrogen atom at the 3-position in the imidazole-1-yl group, or a nitrogen atom at the 2- or 4-position in the 1,2,4-triazole-1-yl group, is quaternized with the group of formula (II) present at said nitrogen atom, said compound being capable of being converted, upon hydrolysis and removal of said group in vivo, into an anti-fungal compound having a quaternized nitrogen atom-free imidazole-1-yl or 1,2,4-triazole-1-yl group.
Examples of such a compound include a compound represented by the formula (Ia) or a salt thereof [hereinafter referred to as a compound (Ia), sometimes].
Examples of the xe2x80x9chydrocarbon groupxe2x80x9d of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 includes aliphatic hydrocarbon group, aromatic hydrocarbon group and aromatic-aliphatic hydrocarbon group. Examples of the aliphatic hydrocarbon group include alkyl group, cycloalkyl group, cycloalkylalkyl group, alkenyl group and alkynyl group. Examples of the alkyl group include straight-chain or branched alkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, etc., and among them, lower alkyl group having 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.) is particularly preferable. Examples of the cycloalkyl group include cycloalkyl group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc., and among them, cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) is particularly preferable. Examples of the cycloalkylalkyl group include those having 4 to 12 carbon atoms, such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc., and among them, cycloalkylalkyl group having 6 to 8 carbon atoms (e.g. cyclopentylmethyl, cyclohexylmethyl, etc.) is particularly preferable. Examples of the alkenyl group include those having 2 to 4 carbon atoms, such as vinyl, propenyl, butenyl, etc., and among them, alkenyl having 2 to 3 carbon atoms (e.g. vinyl, propenyl) is particularly preferable. Examples of the alkynyl group include those having 2 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, etc., and among them, alkynyl having 2 to 3 carbon atoms (e.g. ethynyl, propynyl) is particularly preferable.
Examples of the aromatic hydrocarbon group include those having 6 to 14 carbon atoms, such as phenyl, naphthyl, biphenylyl, anthryl, indenyl, etc., and among them, aryl group having 6 to 10 carbon atoms (e.g. phenyl, naphthyl, etc.) is particularly preferable.
Examples of the aromatic-aliphatic hydrocarbon group include aralkyl groups having 7 to 15 carbon atoms, such as benzyl, phenethyl, phenylpropyl, naphthylmethyl, indanyl, indanylmethyl, 1,2,3,4-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthylmethyl, etc., and among them, aralkyl groups having 7 to 11 carbon atoms (e.g. benzyl, phenethyl, naphthyl-methyl, etc.,) are particularly preferable.
The xe2x80x9cheterocyclic groupxe2x80x9d of the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 is a group obtained by removing one of hydrogen atoms linked to a heterocyclic ring, and such a heterocyclic ring represents a 5- to 8-membered ring containing 1 to several, preferably 1 to 4 hetero atoms (e.g. nitrogen atom (optionally oxidized), oxygen atom, sulfur atom, etc.), or a condensed ring thereof. Specific examples of the heterocyclic ring group include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, indolyl, pyranyl, thiopyranyl, dioxinyl, dioxolyl, quinolyl, pyrido[2,3-d]pyrimidyl, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinyl, thieno[2,3-d]pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl and the like.
Examples of the substituent in the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 include heterocyclic group, oxo group, hydroxy group, C1-6 alkoxy group, C3-10 cycloalkyloxy group, C6-10 aryloxy group, C7-19 aralkyloxy group, heterocyclic ring-oxy group, mercapto group, C1-6 alkylthio group (sulfur atom may be oxidized), C3-10 cycloalkylthio group (sulfur atom may be oxidized), C6-10 arylthio group (sulfur atom may be oxidized), C7-19 aralkylthio group (sulfur atom may be oxidized), a heterocyclic ring-thio group, a heterocyclic ring-sulfinyl group, a heterocyclic ring-sulfonyl group, an amino group, mono-C1-6 alkylamino group, di-C1-6 alkylamino group, tri-C1-6 alkylammonio group, C3-10 cycloalkylamino group, C6-10 arylamino group, C7-19 aralkylamino group, heterocyclic ring-amino group, cyclic amino group, nitro group, halogen atom, cyano group, carboxyl group, C1-10 alkoxy-carbonyl group, C6-10 aryloxy-carbonyl group, C7-19 aralkyloxy-carbonyl group, C6-10 aryl-carbonyl group, C1-6 alkanoyl group, C3-5 alkenoyl group, C6-10 aryl-carbonyloxy group, C2-6 alkanoyloxy group, C3-5 alkenoyloxy group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted carbamoyloxy group, C1-6 alkanoylamino group, C6-10 aryl-carbonylamino group, C1-10 alkoxy-carboxamido group, C6-10 aryloxy-carboxamido group, C7-19 aralkyloxy-carboxamido group, C1-10 alkoxy-carbonyloxy group, C6-10 aryloxy-carbonyloxy group, C7-19 aralkyloxy-carbonyloxy group, C3-10 cycloalkyloxy-carbonyloxy group, optionally substituted ureido group, etc., and they may be the same or different and 1 to 4 substituents may be present. Examples of the xe2x80x9cC1-6 alkoxy groupxe2x80x9d include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, etc.; xe2x80x9cexamples of the C3-10 cycloalkyloxy groupxe2x80x9d include cyclopropyloxy, cyclohexyloxy, etc.; examples of the xe2x80x9cC6-10 aryloxy groupxe2x80x9d include phenoxy, naphthyloxy, etc.; examples of the xe2x80x9cC7-19 aralkyloxy groupxe2x80x9d include benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, benzhydryloxy, etc.; examples of the xe2x80x9cC1-6 alkylthio group (sulfur atom may be oxidized)xe2x80x9d include methylthio, ethylthio, n-propylthio, n-butylthio, methylsulfinyl, methysulfonyl, etc.; examples of the xe2x80x9cC3-10 cycloalkylthio group (sulfur atom may be oxidized)xe2x80x9d include cyclopropylthio, cyclohexylthio, cyclopentylsulfinyl, cyclohexylsulfonyl, etc.; examples of the xe2x80x9cC6-10 arylthio group (sulfur atom may be oxidized)xe2x80x9d include phenylthio, naphthylthio, phenylsulfinyl, phenylsulfonyl, etc.; examples of the xe2x80x9cC7-19 aralkylthio group (sulfur atom may be oxidized)xe2x80x9d include benzylthio, phenylethylthio, benzhydrylthio, benzylsulfinyl, benzylsulfonyl, etc.; examples of the xe2x80x9cmono-C1-6 alkylamino groupxe2x80x9d include methylamino, ethylamino, n-propylamino, n-butylamino, etc.; examples of the xe2x80x9cdi-C1-6 alkylamino groupxe2x80x9d include dimethylamino, diethylamino, methylethylamino, di-(n-propyl)amino, di-(n-butyl)amino, etc.; examples of the xe2x80x9ctri-C1-6 alkylammonio groupsxe2x80x9d include trimethylammonio, etc.; examples of the xe2x80x9cC3-10 cycloalkylamino groupxe2x80x9d include cyclopropylamino, cyclopentylamino, cyclohexylamino, etc.; examples of the xe2x80x9cC6-10 arylamino groupxe2x80x9d include anilino, N-methylanilino, etc.; examples of the xe2x80x9cC7-19 aralkylamino groupxe2x80x9d include benzylamino, 1-phenylethylamino, 2-phenylethylamino, benzhydrylamino, etc.; examples of the xe2x80x9ccyclic amino groupxe2x80x9d include 1-pyrrolidinyl, piperidino, 1-piperazinyl, morpholino, thiomorpholino, etc.; examples of the xe2x80x9chalogen atomxe2x80x9d include fluorine, chlorine, bromine, iodine, etc.; examples of the xe2x80x9cC1-10 alkoxy-carbonyl groupxe2x80x9d include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, norbornyloxycarbonyl, etc.; xe2x80x9cC6-10 aryloxy-carbonyl groupxe2x80x9d include phenoxycarbonyl, naphthyloxycarbonyl, etc.; examples of the xe2x80x9cC7-19 aralkyloxy-carbonyl groupxe2x80x9d include benzyloxycarbonyl, benzhydryloxycarbonyl, etc.; examples of the xe2x80x9cC6-10 aryl-carbonyl groupxe2x80x9d include benzoyl, naphthoyl, phenylacetyl, etc.; examples of the xe2x80x9cC1-6 alkanoyl groupxe2x80x9d include formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, etc.; examples of the xe2x80x9cC3-5 alkenoyl groupxe2x80x9d include acryloyl, crotonoyl, etc.; examples of the xe2x80x9cC6-10 aryl-carbonyloxy groupxe2x80x9d include benzoyloxy, naphthoyloxy, phenylacetoxy, etc.; examples of the xe2x80x9cC2-6 alkanoyloxy groupxe2x80x9d include acetoxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, etc.; examples of the xe2x80x9cC3-5 alkenoyloxy groupxe2x80x9d include acryloyloxy, crotonoyloxy, etc.; examples of the xe2x80x9coptionally substituted carbamoyl groupxe2x80x9d include carbamoyl group which may be substituted with one or two substituents selected from C1-4 alkyl group (e.g. methyl, ethyl, etc.), phenyl group, C1-7 acyl group (e.g. acetyl, propionyl, benzoyl, etc.) and C1-4 alkoxy-phenyl group (e.g. methoxyphenyl, etc.), and cyclic aminocarbonyl group, and specific examples thereof include carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N-(p-methoxyphenyl)carbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 1-piperazinylcarbonyl, morpholinocarbonyl, etc.; examples of the xe2x80x9coptionally substituted thiocarbamoyl groupxe2x80x9d include thiocarbamoyl groups which may be substituted by one or two substituents selected from C1-4 alkyl group (e.g. methyl, ethyl, etc.) and phenyl group, and specific examples thereof include thiocarbamoyl, N-methylthiocarbamoyl, N-phenylthiocarbamoyl, etc.; examples of the xe2x80x9coptionally substituted carbamoyloxy groupxe2x80x9d include carbamoyloxy groups which may be substituted with one or two substituents selected from C1-4 alkyl group (e.g. methyl, ethyl, etc.) and phenyl group, and specific examples thereof include carbamoyloxy, N-methylcarbamoyloxy, N,N-dimethylcarbamoyloxy, N-ethylcarbamoyloxy, N-phenylcarbamoyloxy, etc.; examples of the xe2x80x9cC1-6 alkanoylamino groupxe2x80x9d include acetamido, propionamido, butyramido, valelamido, pivalamido, etc.; examples of the xe2x80x9cC6-10 aryl-carbonylamino groupxe2x80x9d benzamido, naphthamido, phthalimido, etc.; examples of the xe2x80x9cC1-10 alkoxy-carboxamido groupxe2x80x9d include methoxycarboxamido (CH3OCONHxe2x80x94), ethoxycarboxamido, tert-butoxycarboxamido, etc.; examples of the xe2x80x9cC6-10 aryloxy-carboxamido groupxe2x80x9d include phenoxycarboxamido(C6H5OCONHxe2x80x94), etc.; examples of the xe2x80x9cC7-10 aralkyloxy-carboxamido groupxe2x80x9d include benzyloxycarboxamido(C6H5CH2OCONHxe2x80x94), benzhydryloxycarboxamido, etc.; examples of the xe2x80x9cC1-10 alkoxy-carbonyloxy groupxe2x80x9d include methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-butoxycarbonyloxy, tert-butoxycarbonyloxy, n-pentyloxycarbonyloxy, n-hexyloxycarbonyloxy, etc.; examples of the xe2x80x9cC6-10 aryloxy-carbonyloxy groupxe2x80x9d include phenoxycarbonyloxy, naphthyloxycarbonyloxy, etc.; examples of the xe2x80x9cC7-19 aralkyloxy-carbonyloxy groupxe2x80x9d include benzyloxycarbonyloxy, 1-phenylethyloxycarbonyloxy, 2-phenylethyloxycarbonyloxy, benzhydryloxycarbonyloxy, etc.; examples of the xe2x80x9cC3-10 cycloalkyloxy-carbonyloxy groupxe2x80x9d include cyclopropyloxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.; and examples of the xe2x80x9coptionally substituted ureido groupxe2x80x9d include ureido group which may be substituted with 1 to 3 substituents selected from C1-4 alkyl group (e.g. methyl, ethyl, etc.), phenyl group, etc., and specific examples thereof include ureido, 1-methylureido, 3-methylureido, 3,3-dimethylureido, 1,3-dimethylureido, 3-phenylureido, etc.
As the substituent of the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1, for example, C1-6 alkyl group, C3-6 cycloalkyl group, C4-7 cycloalkylalkyl group, C2-3alkenyl group, C2-3 alkynyl group, C6-10 aryl group, C7-11 aralkyl group, etc. are used, in addition to those described above. Examples of the xe2x80x9cC1-6 alkyl groupxe2x80x9d include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.; examples of the xe2x80x9cC3-6 cycloalkyl groupxe2x80x9d include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; examples of the xe2x80x9cC4-7 cycloalkylalkyl groupxe2x80x9d include cyclopropylmethyl, cyclopentylmethyl, etc.; examples of the xe2x80x9cC2-3 alkenyl groupxe2x80x9d include vinyl, propenyl, etc.; examples of the xe2x80x9cC2-3 alkynyl groupxe2x80x9d include ethynyl, propynyl, etc.; examples of the xe2x80x9cC6-10 aryl groupxe2x80x9d includes phenyl, naphthyl, etc.; and examples of the xe2x80x9cC7-11 aralkyl groupxe2x80x9d include benzyl, phenetyl, naphthylmethyl, etc. The number of these substituents of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by R1 is not limited to one, and the substituents may be the same or different plural (2 to 4) substituents.
The heterocyclic group in the substituent of the xe2x80x9chydrocarbon groupxe2x80x9d and xe2x80x9cheterocyclic groupxe2x80x9d, and the heterocyclic group in the heterocyclic ring-oxy group, heterocyclic ring-thio group, heterocyclic ring-sulfinyl group, heterocyclic ring-sulfonyl group and heterocyclic ring-amino group respectively represent a group obtained by removing one of hydrogen atoms linked to the heterocyclic ring, and such heterocyclic ring represents a 5- to 8-membered ring containing 1 to several, preferably 1 to 4 hetero atoms (e.g. nitrogen atom (optionally oxidized), oxygen atom, sulfur atom, etc.), or a condensed ring thereof. Examples of the heterocyclic group include pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolidinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, indolyl, pyranyl, thiopyranyl, dioxinyl, dioxolyl, quinolyl, pyrido[2,3-d]pyrimidyl, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinyl, thieno[2,3-d]pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl, etc. These heterocyclic group may be substituted with 1 to 3 substituents selected from C1-4 alkyl group (e.g. methyl, ethyl, etc.), hydroxyl group, oxo group and C1-4 alkoxy group (e.g. methoxy, ethoxy, etc.).
In the optionally substituted hydrocarbon group or heterocyclic group represented by R1, as the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d, C1-6 alkyl group (examples of the C1-6 alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.) which may be substituted with 1 to 3 substituents selected from hydroxyl, C1-6 alkoxy group, C7-19 aralkyloxy group, C1-6 alkylthio group, C1-6 alkylsulfonyl, C1-6 alkanoylamino group, C1-10 alkoxy-carbonyl group, C7-19 aralkyloxy-carbonyl group, optionally substituted carbamoyl group, C1-10 alkoxy-carboxamido, C7-10 aralkyloxy-carboxamido and heterocyclic group (optionally substituted) is preferable, and specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, 2-benzyloxyethyl, 3-benzyloxypropyl, 1,3-dibenzyloxy-2-propyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2-propyl, methylthiomethyl, methylsulfonylethyl, acetamidomethyl 1-acetamidoethyl, 2-acetamidoethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl, 1-ethoxycarbonylethyl, 2-ethoxycarbonylethyl, 1-methoxycarbonyl-1-methylethyl, 1-ethoxycarbonyl-1-methylethyl, 1-tert-butoxycarbonyl-1-methylethyl, 1-benzyloxycarbonylethyl, 1-benzyloxycarbonyl-1-methylethyl, carbamoylmethyl, N,N-dimethylcarbamoylmethyl, methoxycarboxamidomethyl, ethoxycarboxamidomethyl, tert-butoxycarboxamidomethyl, benzyloxycarboxamidomethyl, 2-ethoxycarboxamidoethyl, 2-furylmethyl, 2-tetrahydrofurylmethyl, 1,3-dioxolan-2-ylmethyl, 1,3-dioxolan-4-ylmethyl, 2-oxo-1,3-dioxolan-4-ylmethyl, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl, 1,3-dioxan-5-ylmethyl, 1-ethoxycarbonyl-1-(2,3,4-trihydroxyphenyl)methyl, 1-acetamido-2-ethoxycarbonyl, 1-acetamido-3-ethoxycarbonylpropyl, 2-acetamido-2-ethoxycarbonylethyl, 3-acetamido-3-ethoxycarbonylpropyl, 1-acetamido-2-carbamoylethyl, 1-acetamido-3-carbamoylpropyl, etc.
Among the above C1-6 alkyl group which may be substituted with 1 to 3 substituents, the most preferable ones include straight-chain or branched C1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.; and straight-chain or branched C1-4 alkyl group substituted with hydroxyl group, C1-6 alkoxy group, C1-10 alkoxy-carbonyl group, heterocyclic group (optionally substituted), etc., such as 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2-propyl, 2-methoxyethyl, 2-ethoxyethyl, 3-benzyloxypropyl, ethoxycarbonylmethyl, 1-ethoxycarbonylethyl, 1-benzyloxycarbonylethyl, 2-furylmethyl, 2-tetrahydrofurylmethyl, 1,3-dioxolan-4-ylmethyl, 2-oxo-1,3-dioxolan-4-ylmethyl, 2,2-dimethyl-1,3-dioxolan-4-ylmethyl, etc.
In the optionally substituted hydrocarbon group or heterocyclic group represented by R1, as the xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d, a heterocyclic group substituted with 1 to 3 substituents selected from oxo group, hydroxyl group, C1-6 alkyl group, C1-6 alkoxy group, etc. are preferable, and specific examples thereof include furyl, thienyl, pyranyl, thiopyranyl, dioxinyl, dioxolyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl, methylfuryl, hydroxyfuryl, methylthienyl, methoxyfuryl, 2-oxo-1,3-dioxolyl, 2,2-dimethyl-1,3-dioxolyl, 2-oxo-1,3-dioxolanyl, 2,2-dimethyl-1,3-dioxolanyl, 2-oxo-1,3-dioxanyl, 2,2-dimethyl-1,3-dioxanyl, etc. Among them, furyl, thienyl, dioxanyl, 2-oxo-1,3-dioxanyl, 2,2-dimethyl-1,3-dioxanyl are particularly preferable.
Examples of the lower alkyl group represented by R2 include lower alkyl group having 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), and methyl is particularly preferable.
As R2, a hydrogen atom or methyl is particularly preferable.
X represents a nitrogen atom or a methine group, and a nitrogen atom is preferable.
Examples of the optionally oxidized sulfur atom represented by X2 includes thio, sulfinyl and sulfonyl.
m and p respectively represent an integer of 0 or 1, and the case where both of them are 0 is preferable.
Examples of the substituent in the xe2x80x9coptionally substituted phenyl groupxe2x80x9d represented by Ar include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), halogenated lower (C1-4) alkyl group (e.g. fluoromethyl, trifluoromethyl, chloromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, etc.) and halogenated lower (C1-4) alkoxy group (e.g. fluoromethoxy, trifluoromethoxy, chloromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, etc.). The substituent is preferably a halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), more preferably fluorine. The number of substituents is preferably 1 to 3, more preferably 1 to 2.
Preferred examples of Ar include halogenophenyl group, halogenated lower (C1-4) alkylphenyl group, halogenated lower (C1-4) alkoxyphenyl group, etc. Examples of the halogenophenyl group include 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2,4,6-trifluorophenyl, 4-bromophenyl, etc. Examples of the halogenated lower (C1-4) alkylphenyl group include 4-trifluoromethylphenyl, etc. Examples of the halogenated lower (C1-4) alkoxyphenyl group include 4-trifluoromethoxyphenyl, 4-(1,1,2,2-tetrafluoroethoxy)phenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(2,2,3,3-tetrafluoropropoxy)phenyl, 4-(2,2,3,3,3-pentafluoropropoxy)phenyl, etc.
Specific preferable examples of Ar are a phenyl group substituted with 1 to 2 halogens, such as 2,4-difluorophenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, 4-bromophenyl, etc. Among them, a phenyl group substituted with 1 to 2 fluorine atoms, such as 4-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, etc. is particularly preferable, and 2-fluorophenyl and 2,4-difluorophenyl are more preferable.
An anion represented by Yxe2x88x92 is that obtained by removing one proton from an organic acid or an inorganic acid, and examples of the organic acid include acetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, toluensulfonic acid, trifluoromethanesulfonic acid trifluoroacetic acid, etc., and examples of the inorganic acid include hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, water, etc. As Yxe2x88x92, an anion obtained by removing one proton from an inorganic acid is preferable. Among them, an anion obtained by removing one proton from a hydro-halogenoic acid such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, etc. is preferable, and an anion obtained by removing one proton from hydrochloric acid, hydrobromic acid, hydroiodic acid, etc. is particularly preferable. Yxe2x88x92 can be defined as a group having a negative charge, and preferred examples thereof include Clxe2x88x92, Fxe2x88x92, Brxe2x88x92, Ixe2x88x92, HSO3xe2x88x92, HSO4xe2x88x92, H2PO4xe2x88x92, OHxe2x88x92, etc. Among them, Clxe2x88x92, Fxe2x88x92, Brxe2x88x92, Ixe2x88x92 are preferable, and Clxe2x88x92, Brxe2x88x92and Ixe2x88x92 are particularly preferable.
Examples of the lower alkyl group represented by R3, R4 and R5 include straight-chain or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. Among them, methyl is particularly preferable.
When R3 and R4, or R4 and R5 are combined to form a lower alkylene group, examples of the lower alkylene group include those having 1 to 4 carbon atoms, such as methylene, ethylene, propylene, butylene, etc. When R3 and R4 are combined to form a lower alkylene group, methylene and ethylene are preferable. When R4 and R5 are combined to form a lower alkylene group, ethylene is preferable.
R3 is preferably a hydrogen atom. Preferably, R4 and R5 are simultaneously hydrogen atoms or methyl groups, or one of them is a hydrogen atom and the other one is a methyl group. More preferably, one of R4 and R5 is a hydrogen atom and the other one is methyl.
Examples of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d or xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d represented by A includes the same one as that described for R1. A is preferably a group of the formula: 
(wherein R6 represents an optionally substituted hydrocarbon group or aromatic heterocyclic group; and Z represents an optionally substituted lower alkylene group or a group of the formula:
xe2x80x94Dxe2x95x90Exe2x80x94
(D and E may be same or different and represent a nitrogen atom or a methine group which may be substituted with a lower alkyl)). Examples of the hydrocarbon group in the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R6 include aliphatic hydrocarbon group, aromatic hydrocarbon group and aromatic-aliphatic hydrocarbon group.
Examples of the aliphatic hydrocarbon group include alkyl, cycloalkyl, alkenyl, alkynyl group, etc. Examples of the alkyl groups include straight-chain or branched one having 1 to 12 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, heptyl, octyl, nonyl, decyl, dodecyl, etc. Among them, a lower alkyl group having 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.) is particularly preferable. Examples of the cycloalkyl groups include cycloalkyl groups having 3 to 8 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Among them, a cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) is particularly preferable. Examples of the alkenyl group include alkenyl group having 2 to 4 carbon atoms. Specific examples thereof include vinyl, propenyl, butenyl, etc. Among them, an alkenyl group having 2 to 3 carbon atoms (e.g. vinyl, propenyl, etc.) is particularly preferable. Examples of the alkynyl group include alkynyl group having 2 to 4 carbon atoms. Specific examples thereof include ethynyl, propynyl, butynyl, etc. Among them, an alkynyl group having 2 to 3 carbon atoms (e.g. ethynyl, propynyl, etc.) is particularly preferable.
Examples of the aromatic hydrocarbon group include aryl group having 6 to 14 carbon atoms. Examples of the aryl group include phenyl, naphthyl, biphenylyl, anthryl, indenyl, etc. Among them, an aryl group having 6 to 10 carbon atoms (e.g. phenyl, naphthyl, etc.) is particularly preferable.
Examples of the aromatic-aliphatic hydrocarbon group include arylalkyl group having 7 to 15 carbon atoms. Specific examples thereof include benzyl, phenetyl, phenylpropyl, naphthylmethyl, indanyl, indanylmethyl, 1,2,3,4-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthylmethyl, biphenylylmethyl, benzhydryl, etc. Among them, an aralkyl group having 7 to 11 carbon atoms (e.g. benzyl, phenetyl, naphthylmethyl, etc.) is particularly preferable.
Examples of the aromatic heterocyclic group in the xe2x80x9caromatic heterocyclic group which may have a substituentxe2x80x9d represented by R6 include aromatic heterocyclic group containing at least one hetero atom selected from nitrogen atom, sulfur atom and oxygen atom. The aromatic heterocyclic group may be condensed with a benzene ring, or 5- or 6-membered heterocyclic ring. Examples of the aromatic heterocyclic group include aromatic heterocyclic group such as imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, thiazolyl, thiadiazolyl, thienyl, furyl, pyrrolyl, pyrazinyl, pyrimidinyl, oxazolyl, isooxazolyl, etc.; and condensed aromatic heterocyclic group such as benzimidazolyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, etc. As the aromatic heterocyclic group, a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 hetero atoms selected optionally from nitrogen atom, sulfur atom and oxygen atom (e.g. imidazolyl, triazolyl, thiazolyl, thiadiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, etc.) is particularly preferable.
Examples of the substituent in the xe2x80x9caliphatic, aromatic or aromatic-aliphatic hydrocarbon group which may have a substituent, or aromatic heterocyclic group which may have a substituentxe2x80x9d represented by R6 include hydroxyl group, optionally esterified carboxyl group (e.g. carboxyl, alkoxycarbonyl having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, etc.), nitro group, amino group, acylamino group (e.g. alkanoylamino having 1 to 10 carbon atoms, such as acetylamino, propionylamino, butyrylamino, etc.), amino group which is mono- or di-substituted with an alkyl group having 1 to 10 carbon atoms (e.g. methylamino, dimethylamino, diethylamino, dibutylamino, etc.), optionally substituted 5- to 6-membered cyclic amino group (e.g. pyrrolidinyl, morpholino, piperidino, pyrazolidinyl, perhydroazepinyl, piperazinyl, 4-benzylpiperazinyl, 4-acetylpiperazinyl, 4-(4-trifluoromethoxyphenyl)-1-piperazinyl, 4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-piperazinyl, 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl, 4-[4-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl, 4-[4-(2.2,3,3,3-pentafluoropropoxy)phenyl]-1-piperazinyl, 4-(4-trifluoromethylphenyl)-4-piperazinyl, etc.), alkoxy group having 1 to 6 carbon atoms (e.g. methoxy, ethoxy, propoxy, butoxy, etc.), halogen atom (e.g. fluorine, chlorine, bromine, etc.), alkyl group having 1 to 6 carbon atoms (e.g. methyl, propyl, butyl, etc.), cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl, cyclopentyl, etc.), halogeno-alkyl group having 1 to 6 carbon atoms (e.g. trifluoromethyl, dichloromethyl, trifluoroethyl, etc.), halogeno-alkoxy group having 1 to 6 carbon atoms (e.g. trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, 2,2,3,3,4,4,5,5-octafluoropentoxy, 2-fluoroethoxy, etc.), oxo group, thioxo group, mercapto group, alkylthio group having 1 to 6 carbon atoms (e.g. methylthio, ethylthio, butylthio, etc.), alkylsulfonyl group having 1 to 6 carbon atoms (e.g. methanesulfonyl, ethanesulfonyl, butanesulfonyl, etc.), alkanoyl group having 1 to 10 carbon atoms (e.g. acetyl, formyl, propionyl, butyryl, etc.), 5- or 6-membered aromatic heterocyclic group (e.g. pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, 1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyridazinyl, etc.) and condensed aromatic heterocyclic group (e.g. benzimidazolyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolyl, indolyl, etc.). Among them, a halogeno-alkoxy group having 1 to 6 carbon atoms and 5-membered aromatic heterocyclic group is preferable, and 1,1,2,2-tetrafluoroethoxy, 2,2,3,3-tetrafluoropropoxy, pyrazolyl (e.g. 1H-pyrazol-1-yl), imidazolyl (e.g. 1H-imidazol-1-yl), 1,2,3-triazolyl (e.g. 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl), 1,2,4-triazolyl (e.g. 1H-1,2,4-triazol-1-yl), tetrazolyl (e.g. 1H-tetrazol-1-yl, 2H-tetrazol-2-yl) are particularly preferable.
The number of the above substituents is preferably 1 to 3, more preferably 1 to 2.
The aliphatic, aromatic or aromatic-aliphatic hydrocarbon groups which may have a substituent, or aromatic heterocyclic group which may have a substituent, which is represented by R6, is preferably an aromatic hydrocarbon group which may have a substituent, more preferably a phenyl group having a substituent. Among them, a phenyl group substituted with a halogeno-alkoxy group having 1 to 6 carbon atoms (e.g. 4-(1,1,2,2-tetrafluoroethoxy)phenyl, 4-(2,2,3,3-tetrafluoropropoxy)phenyl) and a phenyl group substituted with a 5-membered aromatic heterocyclic group [e.g. 4-(1H-pyrazol-1-yl)phenyl, 4-(1H-imidazol-1-yl)phenyl, 4-(1H-1,2,3-triazol-1-yl)phenyl, 4-(2H-1,2,3-triazol-2-yl)phenyl, 4-(1H-1,2,4-triazol-1-yl)phenyl, 4-(1H -tetrazol-1-yl)phenyl, 4-(2H-tetrazol-2-yl)phenyl] are particularly preferable.
The lower alkylene group in the xe2x80x9coptionally substituted lower alkylene groupxe2x80x9d represented by Z include those having 1 to 3 carbon atoms, such as methylene, ethylene, propylene, etc. Among them, ethylene is particularly preferable. The substituent in the xe2x80x9coptionally substituted lower alkylene groupxe2x80x9d is preferably a straight-chain or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. Among them, methyl and ethyl are more preferable, and methyl is particularly preferable.
Preferred examples of the ethylene group which may be substituted with a lower alkyl group, which is represented by Z, include ethylene, 1-methylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-ethylethylene, 1,2-diethylethylene, etc. Among them, ethylene is particularly preferable.
When Z is Dxe2x95x90E, examples of lower alkyl group in the xe2x80x9cmethine group which may be substituted with a lower alkyl groupxe2x80x9d represented by D or E include straight-chain or branched alkyl group having 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.). Among them, methyl is preferable.
Preferred examples of the methine group which may be substituted with a lower alkyl group, represented by D or E, include methine, ethylidyne (xe2x80x94C(CH3)xe2x95x90), propylidyne (xe2x80x94C(CH2CH3)xe2x95x90), butylidyne (xe2x80x94C(CH2CH2CH3)xe2x95x90), etc. Among them, methine and ethylident are preferable, and methine is particularly preferable.
The case where one of D and E is a nitrogen atom and the other is methine; the case where both of D and E are methines; the case where both of D and E are nitrogen atoms; and the case where one of D and E is a nitrogen atom and the other is ethylidyne are preferable. Among them, the case where one of D and E is a nitrogen atom and the other one is methine; and the case where both of D and E are methines are particularly preferable.
Specifically, Z is preferably xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90C(CH3)xe2x80x94, xe2x80x94C(CH3)xe2x95x90Nxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, etc. Among them, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, etc. are more preferable, and xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94 are the most preferable.
As the group represented by the formula: 
for example, 
etc. are preferable. Among them, 
etc. are particularly preferable.
Also, when a reactive atom such as nitrogen atom is present in the optionally substituted hydrocarbon group or optionally substituted heterocyclic group represented by A, a group of formula (II) may be linked to the atom.
When the compound (I) has one or more asymmetric carbon atoms in the molecule, two or more stereoisomers exist, and the stereoisomers and a mixture thereof are also included in the Compound (I).
In the compound represented by the general formula (1a), when A is 
wherein each symbol has the meanings given above, m and p are both 0, R4 is a hydrogen atom and R5 is a methyl group, an optically active compound in which both carbon to which the optionally substituted phenyl group represented by Ar is linked and carbon to which R5 is linked are in the (R) configuration, is particularly preferable.
The formula (Ia) can also be represented by the formula: 
(wherein each symbol is as defined above).
The compounds used in the present invention can be either a hydrate or a nonhydrate.
The compounds used in the present invention are converted in vivo into compounds having an antifungal activity, represented by the formula: 
(wherein each symbol is as defined above)[hereinafter referred to as Compound (III)].
Specific examples of the compounds used in the present invention are shown in Table 1, but are not limited to the exemplified compounds.
The compounds used in the present invention can be produced by introducing a group, which is capable of being eliminated in vivo, into an antifungal compound having an imidazol-1-yl group or 1,2,4-triazol-1-yl group.
Examples of the antifungal compound having an imidazol-1-yl group or 1,2,4-triazol-1-yl group include known azole antifungal compounds such as miconazole, ketoconazole, fluconazole, itraconazole, saperconazole, clotrimazole, D0870, voriconazole, econazole, isoconazole, sulconazole, butoconazole, tioconazole, bifonazole, croconazole, oxiconazole, terconazole, SSY-726, KP-103, Sch-56592, Sch-51048, UR-9746, MFB-1041, UR-9751, UR-9728, UR-9825, ER-30346, T-8581, BAY-W-9279, fenticonazole, omoconazole, flutrimazole, eberconazole, lanoconazole, neticonazole, sertaconazole, genaconazole, etc., but are not limited to known antifungal agents.
The compound (Ia) can be produced, for example, by reacting a compound (III) with a compound represented by the formula (IV): 
(wherein Y1 represents a halogen atom and other symbols are as defined above)[hereinafter referred to as a compound (IV), sometimes] and optionally subjecting the reaction product to anion exchange.
The halogen atom represented by Y1 is preferably chlorine, bromine or iodine.
The reaction between the compound (III) and compound (IV) is usually carried out with or without a solvent which does not inhibit the reaction. As the solvent which does not inhibit the reaction, for example, ketones (e.g. acetone, 2-butanone, 2-pentanone, etc.), sulfoxides (e.g. dimethylsulfoxide, etc.), ethers (e.g. diethyl ether, tetrahydrofuran, dioxane, etc.), nitrites (e.g. acetonitrile, etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, etc.), esters (e.g. ethyl acetate, etc.), amides (e.g. dimethylformamide, acetamide, dimethylacetamide, 1-methyl-2-pyrolidinone, etc.) and ureilenes (e.g. 1,3-dimethyl-2-imidazolidinone, etc.) are used. These solvents can be used alone or in combination thereof in an appropriate ratio.
The compound (IV) is used in an amount of about 1 to 100 equivalent, preferably about 1 to 5 equivalent, based on the compound (III).
The reaction temperature is not specifically limited, but is usually from about 0 to 150xc2x0 C., preferably from about 20 to 120xc2x0 C.
The reaction time is from several minutes to several hundreds hours (e.g. 5 minutes to 100 hours, etc.).
The compound thus obtained can be optionally converted into a compound (Ia) having a desired anion (Yxe2x88x92) by anion exchange. The anion exchange can be carried out by treating with an anion type ion exchange resin, or an alkali metal (e.g. sodium, potassium, etc.) salt of an organic or inorganic acid described above for Yxe2x88x92, in the presence of water, a mixed solvent of water and an organic solvent (e.g. acetone, acetonitorile, tetrahydrofuran, methanol, ethanol, etc.) or organic solvent.
The compound (I) thus obtained can be isolated and purified from the reaction mixture using a per se known means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography, etc.
When the compound (I) used in the present invention has one or more asymmetric carbon atoms in the molecule, two or more stereoisomers exist, but those isomers can be separately prepared, if desired. For example, when the starting compounds (III) and (IV) have an asymmetric carbon atom in the molecule, a single isomer of the compound (Ia) can be obtained by carrying out above reaction using such single isomer. In addition, a single isomer of the reaction compound (Ia) can be obtained by carrying out above reaction using a single isomer of the starting compound (III). Also, when the product is a mixture of two or more kinds of isomers, the product can be separated by using a normal separation method, e.g. separation means such as various chromatographies and fractional recrystallization.
When the compound (III), which is the starting compound of Compound (Ia), is a per se known antifungal agent described above, the production method is known and methods of series of compounds which are useful as an antifungal agent are per se known, for example, the methods described in Japanese Patent Kokai Publication No. Hei 6-293740, Japanese Patent Kokai Publication No. Hei 8-104676 and WO-9625410A. In addition, the production method of the other starting compound (IV) is also known, and the compound can be produced by the method described in Synthesis, page 588 (1971) and Synthetic Communications, Vol. 25, page 2739 (1995), or a manner based on the method.
Compound (I) used in the present invention has an anti-fungal action with low toxicity and can thus be used as an anti-fungal agent. That is, the compound (I) can be used as a preventive or therapeutic agent against fungal infections in mammals (humans, domestic animals, domestic fowls, etc.) caused by various fungi such as microorganisms of the genus Candida (e.g., Candida albicans, Candida utilis, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis etc.), microorganisms of the genus Trichosporon (e.g., Trichosporon asahi etc.), microorganisms of the genus Histoplasma (e.g., Histoplasma capsulatum etc.), microorganisms of the genus Aspergillosis (e.g., Aspergillosis niger, Aspergillosis fumigatus, Aspergillosis flavus etc.), microorganisms of the genus Penicillium (e.g., Penicillium marneffei etc.), microorganisms of the genus Cryptococcus (e.g., Cryptococcus neoformans etc.), microorganisms of the genus Trichophyton (e.g., Trichophyton rubrum, Trichophyton mentagrophytes etc.), microorganisms of the genus Microsporum (e.g., Microsporum gypseum, Microsporum canis etc.), microorganisms of the genus Malassezia (e.g., Malassezia furfur etc.), microorganisms of the genus Sporothrix (e.g., Sporothrix schenckii etc.), microorganisms of the genus Cladosporium (e.g., Cladosporium carrionii etc.), microorganisms of the genus Fonsecaea (e.g., Fonsecaea compactur, Fonsecaea pedrosoi etc.), microorganisms of the genus Phialophora (e.g., Phialophora verrucosa etc.), microorganisms of the genus Rhinocladiella (e.g., Rhinocladiella aquaspersa etc.), microorganisms of the genus Exophiala (e.g., Exophiala jeanselmei etc.), microorganisms of the genus Wangiella (e.g., Wangiella dermatitidis etc.), microorganisms of the genus Coccidioides (e.g., Coccidioides immitis etc.), microorganisms of the genus Epidermophyton (e.g., Epidermophyton floccosum etc.), microorganisms of the genus Paracoccidioides (e.g., Paracoccidioides brasiliensis etc.), microorganisms of the genus Blastomyces (e.g., Blastomyces dermatitidis etc.), and microorganisms of the genus Fusarium (e.g., Fusarium dimerum etc.), preferably against fungal infections by microorganisms of the genera Candida, Cryptococcus, Aspergillosis, and Coccidioides, particularly preferably against fungal infections by microorganisms of the genus Coccidioides. In particular, the compound (I) can be used in humans (immuno-compromised and non-immuno-compromised patients) including patients with AIDS, patients transplanted with organs and patients transplanted with bone marrow, in order to prevent or treat fungal infections [organ mycosis (deep-seated mycosis): hematomycosis, respiratory mycosis (e.g. pulmonary mycosis etc.), gastrointestinal mycosis, urinary tract mycosis, fungal osteomyelitis etc.; deep-seated dermatomycosis: sporotrichosis, chromomycosis; superficial dermatomycosis: trichophytosis (tinea corporis, coxarthrocace, tinea manus, athlete""s foot tinea capitis, tinea kerion, tinea barbae etc.); discoloring desquamation by dermal fungus: hyperkeratosis; candidiasis (oral candidiasis, candidiasis cutis, candidiasis syncosis, chronic mucocutaneous candidiasis etc.); pityriasis versiclor; malassezia folliculitis; tinea unguium; keratomycosis; systemic mycosis; rare tropical mycosis; preferably against hematomycosis, respiratory mycosis, gastrointestinal mycosis, urinary tract mycosis, and fungal osteomyelitis etc.
Specifically, the compound (I) can be used in topical and/or systemic administration for prevention or treatment of e.g. mucous candidiasis (oral candidiasis, esophagus candidiasis, non-invasive bronchus candidiasis, thrush, angular stomatitis, vaginal candidiasis, penile candidiasis etc.), candidiasis cutis (candidiasis erosio interdigitalis, candidiasis interytigo, candidiasis periproctis, eczematoid candidiasis dermatis, candidiasis onychitis, candidiasis perionychia, candidiasis inflammation of external auditory meatus, dermatosis of candidiasis sepsis, universal superficial candidiasis, candidiasis granuloma, congential skin candidiasis, candidid, candidiasis sycosis, erythema myceticum infantile etc.), chronic mucosal skin candidiasis, disseminated candidiasis and visceral candidiasis [respiratory candidiasis (bronchial candidiasis, pulmonary candidiasis, pneumonia etc.), digestive system candidiasis, candidemia, candidemia, candidiasis endocarditis, candidiasis myocarditis, urinary system candidiasis, candidiasis of eyes, central nervous system candidiasis, articular and bony candidiasis, candidiasis peritonitis, hepatic candidiasis, intrauterine candidiasis"" etc.], trichosporosis by microorganisms of the genus Trichosporon, acute lung histoplasmosis by microorganisms of the genus Histoplasma, chronic lung histoplasmosis and disseminated histoplasmosis, penicilliosis by microorganisms of the genus Penicillium, respiratory aspergillosis by microorganisms of the genus Aspergillosis [allergic aspergillosis, bronchial aspergillosis, aspergilloma, pulmonay aspergillosis (acute invasive aspergillosis, chronic necrotic pulmonay aspergillosis), aspergillosis empyema], disseminated aspergillosis, central nervous system aspergillosis, aspergillosis endocarditis, aspergillosis myocarditis, aspergillosis pericarditis, aspergilloma, aspergillosis of external auditory meatus, onychia of aspergillosis, aspergillosis inflammation of perionychium, aspergillosis corneitis, aspergillosis endophthalmitis, dermal aspergillosis, accessory sinus orbita aspergillosis; lung cryptococcosis by microorganisms of the genus Cryptococcus, central nervous system cryptococcosis, cryptococcosis meningitis, dermal and mucosal cryptococcosis, bony and articular cryptococcosis, lymph node cryptococcosis, systemic cryptococcosis and cryptococcosis of hematopoletic organs; ringworm of scalp, tinea captis, favus, Celsus"" kerion, tinea barbae, spotted phlyctenula tinea, eczematous tinea, anfractuous tinea, athlete""s foot, tinea unguium, trichophytid and tinea, granuloma trichophyticum etc. by microorganisms of the genera Trichophton, Microsporum and Epidermophyton; pityriasis versicolor, Malassezia folliculitis, folliculitis, intertrigo, seborrhea, dacryocystitis etc. by microorganisms of the genus Malassezia; sporotrichosis etc. by microorganisms of the genus Sporotrichum; Chromobacterium diseases (infections with black branched bacteria) by microorganisms of the genera Cladosporium, Fonsecae, Phialophora, Rhinocladiella, etc.; Chromobacterium diseases (infections with black hypha bacteria) by microorganisms of the genera Exophiala and Wangiella; coccidioidomycosis by microorganisms of the genus Coccidioides, para-coccidioidomycosis by the genera Para-coccidioides, blastomycosis by microorganisms of the genus Blastomyces; and Fusarium diseases by microorganisms of the genus Fusarium, and further the compound (I) can be used for prevention and treatment of atopic. dermatitis. Further, the composition of the present invention can contain two or more compounds (I), and may also contain other compounds having an anti-fungal action in addition to the compound (I).
The composition of the present invention comprising compound (I) and a saccharide can be produced by mixing compound (I) with the saccharide, or dissolving or suspending either or both of them in a suitable solvent such as water and then mixing both of them, followed by lyophilization thereof. The saccharide includes e.g. monosaccharides such as fructose and glucose, disaccharides such as maltose, cellobiose, gentiobiose, melibiose, lactose, turanose, sophorose, trehalose, isotrehalose, isosaccharose and white sugar, sugar alcohols such as mannitol, sorbitol, xylitol and inositol. In particular, maltose, lactose, trehalose, white sugar, mannitol and inositol are preferable, and inositol and trehalose are the most preferable.
Although the ratio of compound (I) to the saccharide mixed is not particularly limited, the amount of the saccharide is usually 0.001 to 1000 parts by weight, preferably 0.01 to 100 parts by weight, more preferably 0.1 to 20 parts by weight and most preferably 0.1 to 10 parts by weight relative to 1 part of compound (I).
The lyophilized product described in item (2) above can be produced in a known lyophilization method by lyophilizing an aqueous solution containing both compound (I) and the saccharide dissolved in a suitable solvent (e.g. a mixed solvent of water and alcohol). In the aqueous solution before lyophilization, the concentration of compound (I) is usually 0.01 mg/ml to 500 mg/ml, and the concentration of the saccharide is usually 0.01 mg/ml to 1,000 mg/ml. Lyophilization is conducted usually under the condition of 0.01 to 1.0 Torr, preferably 0.05 to 0.5 Torr, for 12 to 100 hours. Specifically, said aqueous solution is frozen at its eutectic point or less, and after the shelf temperature is gradually increased to a primary lyophilization temperature under vacuum in a drying chamber, the sample is subjected to primary lyophilization at the same temperature, and after the primary lyophilization is finished, the shelf temperature is gradually increased to a secondary drying temperature, and secondary lyophilization is carried out. The shelf temperature in the first and second lyophilization may be the same or different. The first lyophilization temperature is a temperature at which noticeable water or ice is eliminated, while the second lyophilization temperature is a temperature at which water which is hardly removable due to its strong bonding to the molecule can be completely eliminated. For example, the primary and secondary lyophilization temperatures for 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolydinyl]butyl]-1H-1,2,4-triazolium chloride are about xe2x88x9210xc2x0 C. and about 45xc2x0 C., respectively.
The lyophilized product thus obtained can maintain compound (I) stably for a long time and can be used as a pharmaceutical preparation for injection or as an agricultural anti-fungal agent.
Depending on use of the lyophilized product, other ingredients may be mixed therewith. For use thereof as e.g. a pharmaceutical preparation for injection, an agent (e.g. salts such as common salt) rendering the solution isotonic by regulating osmotic pressure, a pH-adjusting agent (e.g. citric acid buffer) etc. may be mixed with the aqueous solution before lyophilization, and before lyophilization, the aqueous solution containing both compound (I) and the saccharide may be filtered with 0.22 xcexcm filter or treated to remove pyrogen to make the solution aseptic.
The lyophilized product for injection can be dissolved in injection water or intravenous infusion (e.g., physiological saline, glucose etc.) just before administration and used as an injection such as intravenous injection, subcutaneous injection, intramuscular injection or intravenous drip infusion, or as eye drops. This solution in injection water or in intravenous infusion is sufficiently stable. In this case, it is preferable that the concentration of compound (I) in the solution is e.g. about 0.01 mg/ml to 20 mg/ml, while the concentration of the salt is about 0.01 mg/ml to 400 mg/ml.
The dose of the composition of the present invention is varied depending on the state of infections, the administration route etc., but for oral administration into an adult patient (weight: 50 kg) for the purpose of treatment of candidiasis, the amount of compound (I) therein is about.0.01 to 100 mg/kg/day, preferably about 0.1 to 50 mg/kg/day and more preferably about 0.5 to 10 mg/kg, and for administration as an injection, the amount of compound (I) is about 0.01 to 100 mg/kg/day, preferably about 0.05 to 50 mg/kg/day and more preferably about 0.1 to 5 mg/kg/day.
When the composition of the present invention is used as an agricultural anti-fungal agent, the composition can be mixed with a suitable solid carrier (e.g., diluent, fillers) and used in the form of preparations such as powder, granules etc. These preparations can be prepared by any process known in the art. The amount of compound (I) used is about 250 to 150 g, preferably about 40 to 80 g per are of a paddy field in controlling e.g. rice blast disease.
Two or more compounds (I) may be used in combination, or single compound (I) may be used in combination with other agricultural anti-fungal compounds.
The following Reference Examples, Examples, Preparation Examples and Experimental Examples illustrate the present invention in detail, but are not to be construed to limit the scope thereof.
1H-NMR spectrum is measured by a Varian Gemini 200 (200 MHz) type spectrometer using tetramethylsilane as an internal standard, and all xcex4 values were represented by ppm. The numerical value described in ( ) for the mixed solvent is a volume mixing ratio of each solvent. xe2x80x9c%xe2x80x2 sxe2x80x9d are by weight unless otherwise stated. A ratio of the solvent in silica gel chromatography represents a volume ratio of solvents to be mixed.
The symbols in the Examples have the following meanings.
s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, tt: triple triplet, m: multiplet, br: broad, J: coupling constant.